Project Summary/Abstract Viral infections of the central nervous system (CNS) can lead to debilitating diseases such as encephalitis that result in long-lasting, often severe, neurological deficits. In such cases, neuropathogenesis usually occurs coincident with the acute infection. Viral persistence and latency within the CNS is generally not considered a feature of neurotropic RNA viruses; for these viruses, it is generally assumed that sterile clearance occurs soon after an acute challenge. However, RNA viruses have been associated with CNS diseases that appear months to years after initial infection, raising the possibility that viral reactivation and resultant pathogenesis may recur long after the acute phase is resolved. Consistent with this hypothesis, measles virus (MV) RNA and mRNA persist in the CNS of elderly individuals who died of natural causes, implicating retention of viral genomes for decades after primary exposure. Our laboratory has recently shown that MV-infected immunocompetent mice, engineered to express a MV receptor in CNS neurons, functionally control the infection with no lasting pathogenic consequences. Remarkably, however, viral RNA and mRNA persist in neurons of these mice for up to two years after viral challenge. When the adaptive immune response is suppressed in these mice, levels of MV RNA, mRNA, and protein rebound within the CNS, suggesting a contribution of the host immune response, perhaps mediated by T resident memory cells, in restricting viral replication in the CNS. Therefore, the goals of this proposal are to identify how effector lymphocytes restrict MV replication in neurons, and to characterize the state and localization of MV within these quiescently infected cells. We view these studies as essential proof-of- principle efforts to shed light on the biology and pathogenesis of long-lasting neurotropic RNA virus infections, and expect them to be pivotal for the design of therapeutic strategies to prevent their reactivation in humans who have been exposed to these pathogens earlier in life, and who become immunocompromised due to age, infection, or chemotherapy.